Impact of smoking on the effectiveness of different non-small-cell lung cancer therapies

Smoking reshapes tumor genetics, host immunity, and drug metabolism in non-small-cell lung cancer (NSCLC), yet its therapy-specific impact is often overlooked. This review sought to clarify how current, former, and never smokers respond to each major NSCLC modality and to outline opportunities for treatment optimization.

A systematic search of PubMed, Web of Science, and Google Scholar up to April 2025 identified 146 high-quality trials, cohorts, and meta-analyses that reported outcomes by smoking status. Hazard ratios, response rates, and complication data, and random-effects meta-analyses were performed.

Immune-checkpoint inhibitors improved overall survival across all smoking groups (pooled HR_OS =0.74), although active smokers exhibited shorter response durability because of faster drug clearance and persistent immune dysfunction despite higher tumor-mutational burden and programmed death-ligand 1 (PD-L1) expression. Never-smokers achieved markedly better progression-free survival with EGFR tyrosine-kinase inhibitors [hazard ratio (HR) 0.32 vs. 0.54 in smokers], whereas ALK inhibitors showed little disparity. Smoking attenuated chemotherapy and radiotherapy benefits through cytochrome-P450 induction, tumor hypoxia, and enhanced DNA repair, and it increased postoperative pulmonary-complication rates two- to five-fold after lung resection; cessation ≥8 weeks reduced but did not eliminate this surgical risk.

Smoking status is a potent, modifiable determinant of NSCLC outcomes. Embedding structured cessation programs, tailoring dose or schedule, and incorporating smoking-informed molecular profiling into routine care could heighten efficacy and reduce toxicity. Future trials should stratify participants by detailed tobacco history to advance truly personalized, behavior-integrated oncology.